Open access peer-reviewed chapter

Novel N-Heterocyclic Carbene Silver (I) Complexes: Synthesis, Structural Characterization, Antimicrobial, Antioxidant and Cytotoxicity Potential Studies

Written By

Ichraf Slimani, Khaireddine Dridi, Ismail Özdemir, Nevin Gürbüz and Naceur Hamdi

Submitted: October 14th, 2021 Reviewed: December 9th, 2021 Published: February 16th, 2022

DOI: 10.5772/intechopen.101950

From the Edited Volume

Carbene

Edited by Satyen Saha and Arunava Manna

Chapter metrics overview

77 Chapter Downloads

View Full Metrics

Abstract

Nowadays, N-heterocyclic carbene-based silver-complexes Ag(I) have been widely used as an organometallic drug candidate in medicinal and pharmaceutical chemistry researches due to their low toxicity. Due to the success of Ag(I) complexes in biological applications, interest in the synthesis and applications of such compounds is increasing rapidly. Therefore, in this study, a series of unsymmetrical N,N-disubstituted benzimidazolium salts were synthesized as N-heterocyclic carbene (NHC) (2a-2j). The interaction of these benzimidazolium salts having their two nitrogen atoms substituted by bulky groups with Ag2O in DMF has been carried out to afford Ag(I) complexes and characterized by 1H NMR, 13C NMR, FT-IR and elemental analyses. The antimicrobial activity of Ag(I) complexes was tested against some standard culture collections of Gram-negative, Gram-positive bacterial strains and Fungal strains, which are the most frequently isolated among the society and hospital-acquired infectious microorganisms as potential metallopharmaceutical agents. The Ag-NHC complexes showed effective antimicrobial activity against microorganisms with MIC values between 0.0024 and 1.25 mg/ml. Moreover, these Ag-NHC complexes exhibited significant antioxidant activities. In addition, of benzimidazoles salts 2,4 and Ag(I) complexes 3,5 were screened for their antitumor activity. The highest antitumor activity was observed for 3e and 3d Complexes.

Keywords

  • N-heterocyclic carbene
  • benzimidazolium salts
  • silver (I)-NHC complexes
  • antimicrobial
  • antioxidant and antitumor activities

1. Introduction

N-Heterocyclic carbenes (NHCs) are nitrogen-based heterocyclic compounds containing a divalent carbon atom. Previously, many researchers tried numerous synthetic methods to isolate the stable NHCs, but they were not successful until the first stable free-carbene was isolated in 1991 as a crystal solid by Arduengo and coworkers [1]. Since then, the number of studies in carbene chemistry has increased considerably, and has become stable in research laboratories throughout the world. Today, NHCs are one of the important classes of ligands for coordination chemistry. NHCs have strong σ-donating but, weak π-accepting properties, which show excellent support to stabilize various oxidation states of transition-metal. Also, they can provide steric and electronic properties for the optimal design of transition-metal complexes [2, 3, 4, 5, 6, 7, 8]. The modification at the nitrogen atoms of the NHCs significantly influence the reactivity and binding affinity of the ligand; thus, NHCs make the strong metal-carbon bond with different metals. Transition-metal complexes of NHCs are used as strong-, reactive- and selective-catalysts in many chemical reactions. Initially, the metal-NHC complexes were used extensively as a catalyst in organic transformations such as C-C, C-heteroatom cross-couplings, and C-H functionalization [9, 10, 11, 12]. Also, in recent years, transition metal-NHC complexes containing Au, Pd, Cu, Ru, Pt, Ag, Rh metals have been widely used in medicine and pharmacy as the potential metallopharmaceutical agents against AMR [13, 14, 15, 16]. Although, most of the organometallic drug research has focused on platinum- and gold-containing compounds, carbene-based silver-compounds stand out in the class of organometallic drugs owing to their low toxicity, easy synthesis, stability and limited possibility of side effects. Ag(I) complexes possess several properties, ranging from antibacterial, anticancer, anti-inflammatory and antiseptic to antineoplastic activity [17]. Ag(I) complexes have been recently at the focal point with increased attention due to their usually strong antimicrobial and anticancer properties, and have more effective than other transition-metal complexes, and also, they have low toxicity for humans. Ag(I) complexes also promise to be agents capable of overcoming AMR and beating antibiotic resistant bacteria, fungi and parasites [18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34]. Heterocyclic molecules are an important family of organic chemistry with a wide range of applications [35]. Although, this family is generally known for its agrochemical and veterinary applications, it is also used as a corrosion inhibitor, sanitizer, and dyestuff [36]. Many heterocyclic molecules such as favipiravir have also important pharmaceutical applications [37, 38]. For example, ribavirin is an N-heterocyclic molecule that is used in the treatment of COVID-19 [39]. The reasonable results obtained from bioactivity studies have enabled them to be a family that is frequently used in pharmaceutical chemistry [40]. NHCs, which are known for their high catalytic activity, are easily synthesized and modified [41, 42]. NHC metal complexes have become a popular research area with the frequent usage of metals in drug molecules. In our previous works, we concluded that the presence of electron-donating and bulky substituents attached to the nitrogen of the carbene ligand increases the antimicrobial activity of the silver complexes. These exciting results have led us to further investigate the antimicrobial properties of silver-NHCs. In this regard, herein, we now report the synthesis of novel NHC salts and their Ag(I) complexes and investigate their antimicrobial, antioxidant and cytotoxic activities. All salts and complex structures were characterized by elemental analysis, Fourier transforms infrared (FTIR), 1H and 13C nuclear magnetic resonance (NMR) spectroscopies.

Advertisement

2. Results and discussion

2.1 Preparation of benzimidazolium salts

Nitrogen-containing heterocyclic compounds received great attention because of their wide range of catalytic and pharmacological properties in organometallic chemistry. In this study, benzimidazoles salts (2a-j) prepared by the reaction of N-(isobutyl)-benzimidazole (1) with various aryl chloride in DMF at 80°C for 24 h. The reaction pathway is shown in Figure 1.

Figure 1.

Synthesis of the benzimidazoles salts (2a-j).

The NMR spectra of all compounds were run in δ-CDCl3. The acidic protons (NCHN) of the benzimidazolium salts (2a-j) were detected in the 1H NMR spectra at 12.07, 11.81, 11.44, 11.08, 11.29, 10.48, 12.05, 11.34, 11.52, and 11.95 ppm, respectively, as a typical singlet. These are in agreement with values in the associated literature [43, 44, 45, 46, 47, 48, 49]. The methyl protons of the isopropyl group on the benzimidazolium salts (2a-j) were observed between 0.98 and 1.06 in the form of doublets, whereas the methyl protons of the benzimidazolium salts (2a-j) were signaled at 2.24–2.44 ppm as singlets. The isopropyl group H2’ protons on all the benzimidazolium salts were visualized as septets in the interval 2.34–2.44 ppm. Also, in the 1H NMR spectra of (2a-j), the H1’ protons appeared between 4.32–4.51 ppm while the H1” protons were detected as typical singlet between 5.80–6.90 ppm. The signals detected in the range of 6.94–8.64 ppm are assigned to the aromatic protons of benzimidazolium salts (2a-j). In 13C NMR spectra, the N-HCN (C2) carbene peak of benzimidazole salts (2a-j) was assigned between 141.91–144.02 ppm.

Ag2O and Benzimidazolium salts (2a-j) were reacted in dichloromethane at room temperature under dark and Ag(I)-NHC complex (3a-j) was obtained in very good yields. The Ag(I) complexes (3a-j) have good solubility in polar solvents and are stable in the air and towards the moisture. The synthetic route for the synthesis of Ag(I)-NHC complex (3a-j) is shown in Figure 2. In the 1H NMR spectra, the acidic imino proton of benzimidazolium salts (NCHN) were not observed between δ 10.48–12.07 ppm. Similarly, in the 13C NMR spectra, imino carbon of benzimidazolium salts (NCHN) was not observed between δ 141–144 ppm.

Figure 2.

Synthesis of silver(I) complexes3a-j.

At the same time, the formation of the Ag(I) complexes (3a-j) was proven by IR spectra, which showed CN bond vibrations in the range of 1400–1591 cm—1. The antibacterial and antioxidant activities of all the synthesized benzimidazolium salts (2a-j) and their corresponding Ag(I) complexes (3a-j) were evaluated as per details given in the following text.

Advertisement

3. Biological activities

It is known that the number of silver centers plays an important role in biological activity. The competence of the biological potential of silver (I) complexes is essentially influenced by the type of ligands bound to the metal centre. The presence of lipophilic groups such as alkyl chains on the NHC ligand enhances the lipophilic nature of the silver complex, which helps it penetrate the cell wall easily. The complexes have shown antibacterial activity to different extents, according to the type of ligand.

Benzimidazolium salts (2a-j) and Ag(I) complexes (3a-j) were tested against bacterial strains both Gram-positive and negative bacterial. As it was reported in the literatures [50, 51, 52], the DMSO did not exhibit any antimicrobial activity. The results are reported [27, 28, 29, 30, 31] in Table 1. Generally, all the Ag(I) complexes exhibited antibacterial activity against all bacterial strains except, the two compounds 3aand 3iwere not active against Listeria monocytogenes. While all the benzimidazolium salts (2a–j) performed a good antibacterial potential against the test Gram-negative and positive strains and showed bacterial inhibition in the range 14 ± 0.5–36 ± 0.2 mm. There was rarely a difference in the antibacterial activity of benzimidazolium salts (2a-j) and Ag(I) complexes (3a-j) between all bacterial strains, except that with Micrococcus luteusstrains, the tested compounds showed better antibacterial potential than others. The observed antibacterial activity of tested complexes is comparable to that of our previous silver complexes [53, 54, 55]. The MIC values of tested Ag(I) complexes and their starting material against L. monocytogenesATCC 19117, Salmonella TyphimuriumATCC 14,028 and M. luteusare presented in Table 2.

Microorganisms
Compounds
Micrococcus luteus
LB 14110
Listeria monocytogenes
ATCC 19117
Salmonella Typhimurium
ATCC 14028
Staphylococcus aureus
ATCC 6538
Pseudomonas
aeruginosa
2a20 ± 0.614 ± 0.518 ± 0.5416 ± 0.2516 ± 0.13
2b22 ± 0.615 ± 0.618 ± 0.517 ± 0.317 ± 0.14
2c35 ± 0.516 ± 0.218 ± 0.518 ± 0.522 ± 0.2
2d30 ± 0.514 ± 0.516 ± 0.1018 ± 0.1116 ± 0.19
2e25 ± 0.3322 ± 0.518 ± 0.518 ± 0.1820 ± 0.45
2f36 ± 0.216 ± 0.318 ± 0.0520 ± 0.120 ± 0.4
2g28 ± 0.3216 ± 0.522 ± 0.4418 ± 0.1522 ± 0.5
2h30 ± 0.416 ± 0.216 ± 0.220 ± 0.218 ± 0.2
2i30 ± 0.222 ± 0.222 ± 0.322 ± 0.220 ± 0.4
2j34 ± 0.4422 ± 0.522 ± 0.1522 ± 0.320 ± 0.25
3a20 ± 0.2222 ± 0.2218 ± 0.0518 ± 0.22
3b18 ± 0.220 ± 0.216 ± 0.320 ± 0.218 ± 0.2
3c16 ± 0.218 ± 0.318 ± 0.2216 ± 0.016 ± 0.5
3d22 ± 0.216 ± 0.214 ± 0.220 ± 0.216 ± 0.2
3e18 ± 0.218 ± 0.2218 ± 0.3318 ± 0.2318 ± 0.22
3f30 ± 0.422 ± 0.730 ± 0.425 ± 0.219 ± 0.17
3g22 ± 0.316 ± 0.422 ± 0.418 ± 0.218 ± 0.2
3h10 ± 0.414 ± 0.512 ± 0.1014 ± 0.1516 ± 0.10
3i32 ± 0.3216 ± 0.1518 ± 0.118 ± 0.15
3j20 ± 0.418 ± 0.518 ± 0.2418 ± 0.518 ± 0.16

Table 1.

Zone of bacterial inhibition measured in mm of the synthesized salts and silver complexes [27, 28, 29, 30, 31].

Microorganism indicatorCompoundsMIC (mg/ml)
Listeria monocytogenes
ATCC 19117
2h1.25
2j0.625
3f0.0048
Ampicillin0.039
SalmonellaTyphimurium
ATCC 14028
2h1.25
2j0.039
3f0.0024
Ampicillin0.625
Micrococcus luteus2h0.3125
2j0.3125
3f0.0024
Ampicillin0.0195

Table 2.

Minimal bacterial inhibitory concentration measured in mg/mL of benzimidazoles salts and Ag(I) complexes [27, 28, 29, 30, 31].

3.1 Minimum inhibitory concentration (MIC) determination

The antimicrobial activity of compounds 2 h, 2j, and 3fhas been reported based on MIC values, which are defined as the lowest concentration of an antimicrobial that visibly inhibits bacterial growth after overnight incubation. As shown in Table 2, MIC values ranged between 0.0024 and 0.3125 mg mL−1 for M.luteus LB 14110. Listeria monocytogenes ATCC 19117 shows the range from 0.0048 to 1.25 mg mL−1 and for Salmonella typhimurium ATCC 14028 the MIC values varied between 0.0024 and 1.25 mg mL−1. The Ag complex 3fshowed better activity than ampicillin against Micrococcus luteus as well as for Salmonella Typhimurium with an MIC of 0.0024 mg/mL. Whereas, L. monocytogenes exhibited an MIC value of 0.0048 mg/mL using the same complex. The MICs of the other compounds were in the range tested.

Advertisement

4. Antioxidant activities

The scavenging activity of the synthesized of the NHC precursors [27, 28, 29, 30, 31] is in Figure 3 and Ag(I) complexes with DPPH (1,1-diphenyl- 2-picrylhydrazyl) is represented in Figure 4.

Figure 3.

DPPH radicals scavenging activity of benzimidazoles salts2a,2d,2g.

Figure 4.

DPPH radicals scavenging activity of (Ag-NHC) complexes3d,3g.

The antioxidant activities for compounds 2a, 2d, 2g, 3g, and 3dare summarized in Figures 3 and 4. The results analysis indicated that the antiradical activity profiles obtained from the tested synthetic products 3gand 3dhad improved and demonstrated antioxidant activity compared to the other products. At a concentration used (0.0625 mg/ml), 2dshowed the lowest free radical activity when compared to both gallic acid and BHT (butylated hydroxytoluene). Similarly, compounds 2a, 2gand 3d, at a concentration of 0.0625 mg/ml, had lower radical activity than gallic acid as well as BHT (butylated hydroxytoluene). 2a, 2d, 2g, 3gand 3drevealed significant DPPH activity over synthetic antioxidants at the concentration of 1 mg/ ml.

Advertisement

5. Cytotoxic activities

The anticancer activities of benzimidazole salts 2a-jand Ag(I) complexes 3a-jwere investigated against breast cancer MCF-7, MDA-MB-231 cells. The results are listed in Table 3. The cytotoxicity of 3iand 3fwas significantly higher against MCF7 cells as shown in Table 3 with IC50 values of 0.68 and 0.6 mg/ml, respectively, than its activity against MDA-MB-231 cells. Additionally, compound 3jexhibited cytotoxicity towards MCF7 and MDA-MB-231 cells equal to 2.3 and 3.4 mg/ml. whereas compounds 2aand 2dwere not active against MCF7 and MDA-MB-231. The compounds 2f-jhad showed IC50 values higher than 100 mg/ml.

benzimidazoles salts 2a-j and Ag(I) complexes 3a-jAnticancer activity LC50in mg/ml
MCF7 MDA-MB-231
3aMCF7MDA-MB-231
3b4.2 ± 3.62.5 ± 4.3
3c3.1 ± 3.12.6 ± 5.9
3d1.7 ± 3.116 ± 2.8
3e4.3 ± 1.80.0 ± 00
3f0.68 ± 3.21.93 ± 2.6
3 g1.3 ± 4.13.3 ± 2.9
3 h2.0 ± 3.22.8 ± 2.9
3i0.61 ± 3.11.95 ± 2.5
3j1.3 ± 4.13.4 ± 2.9
2a2.0 ± 3.22.7 ± 2.8
2bNANA
2c3.1 ± 5.96.3 ± 3.2
2dNANA
2e0.6 ± 2.93.1 ± 5.9
2fHigher than 100 mg/mlHigher than 100 mg/ml
2 gHigher than 100 mg/mlHigher than 100 mg/ml
2 hHigher than 100 mg/mlHigher than 100 mg/ml
2iHigher than 100 mg/mlHigher than 100 mg/ml
2jHigher than 100 mg/mlHigher than 100 mg/ml
TetracyclineaNTNT

Table 3.

Anticancer activities of synthesized benzimidazoles salts 2a-jand Ag(I) complexes 3a-j[27, 28, 29, 30, 31].

Values are mean value ± standard deviation of three different replicates. The concentration was 30 mg, NT: not tested, NA: not active.

On the other hand, benzimidazolium salts (4a-4j) have been synthesized following our previous work [56, 57] (Figure 5). The 1H NMR spectra of the benzimidazolium salts (4a-j) showed an acid proton H2 which appeared as a typical singlet at 12.02, 11.80, 12.02, 11.77, 11.61, 11.79, 12.15, 12.27, 11.46 and 11.26 ppm, respectively.

Figure 5.

Synthesis of benzimidazoles salts4a-j.

The protons of the aromatic group on benzimidazolium salts (4a-4j) were identified in the range of 6.30–8.02 ppm. The H2’ protons of the isobutyl group were seen as heptate in the range between 2.25 and 2.44 ppm. The signals resonated between 0.98 and 1.04 are assigned to protons of isobutyl group Hab on benzimidazolium salts (4a-4j). Further evidence for the formation of benzimidazolium salts (4a-4j) is provided by the peak of C2 of the carbons as typical singlets in the range 144.1–144.5 ppm. The 13C NMR spectra showed also aromatic carbons of benzimidazolium salts (4a-4j) in the range of 105.8–153.8 ppm. The terminal carbons Cab of the isobutyl group of all benzimidazolium salts (4a-4j) showed peaks in the region 19.3–19.9 ppm. While the carbons C2’ of the isobutyl group were identified between 28.6–28.9 ppm. These values are consistent with those in the corresponding literature [58].

The synthesis of Ag(I) complexes was performed in the absence of light. The reaction is carried out between benzimidazolium salt with 1 equiv. Ag2O in dichloromethane at room temperature. The Ag(I) complex was produced as a crystalline solid (Figure 6). The reaction was monitored by 1H NMR spectroscopy in δ-CDCl3 and demonstrated that the benzimidazolium salts were fully converted to silver complexes in moderate yields (72–93%).

Figure 6.

Synthesis of Ag-NHC4a-j.

The Ag(I) complexes are stable in air and moisture with high solubility in polar solvents. The formation of the silver carbene complexes was proved by the absence of an NCHN proton peak in their 1H NMR spectra, which confirms the complete conversion to Ag(I) complexes (5a-5j).

The successful formation of the silver carbene complexes was also indicated by the presence of the characteristic carbon (NCHN) signals in the bottom region of the field in comparison with those of the corresponding benzimidazolium salts (4a-4j). For example, it was observed at 186.7 ppm for complex 5j. However, the rest of the carbon signal for the rest of the complexes was not observed. These values are in agreement with reported by Asekunowo et al. [59, 60] who have reported the synthesis of a series of monocarbon silver halides [R2NHC]-AgCl and demonstrated the effect of halide ions and solvent on the structural formulas of Ag(I) complexes. In addition, the formation of the Ag(I) complexes (5a-5j) was verified by the IR spectra, which showed vibrations of the CN bond at 1567, 1583, 1450, 1467, 1433, 1437, 1450, 1433, 1600 cm−1, respectively.

Advertisement

6. Biological, cytotoxic and antibacterial activities

All the synthesized benzimidazolium salts (4a-4j) and their corresponding Ag(I) complexes (5a-5j) were investigated for antibacterial against the gram (+)/(−) bacteria. The DMSO did not exhibit any antimicrobial activity as reported earlier [61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73].

All tested compounds exhibited antibacterial activities against all bacteria strains. Compound 5iwas found the most effective in inhibiting the growth of the Micrococcus luteusLB 14110. Also, for compounds 5c, 5 hand 5fshowed excellent activities against the same bacteria strain. Moreover, NHC precursors (4a–j) were less active than corresponding silver complexes (5a-5j) against all bacteria strains. The complexes showed an increased antibacterial activity due to the synergistic effect that increases the lipophilicity of the complexes, which facilitates the penetration of the complexes through the cell’s membrane.

6.1 MIC determination

The MIC values of tested silver complexes and their starting material against Listeria monocytogenesATCC 19117, SalmonellaTyphimurium ATCC 14028 and M. luteusare presented in Table 4.

Microorganism indicatorCompoundsMIC (mg/ml)
Listeria monocytogenes
ATCC 19117
4h1.25
4j0.635
5f0.0058
Ampicillin0.049
SalmonellaTyphimurium
ATCC 14028
4h1.26
4j0.041
5f0.0034
Ampicillin0.635
Micrococcus luteus4h0.3225
4j0.3125
5f0.0034
Ampicillin0.0195

Table 4.

Minimal bacterial inhibitory concentration (MIC) of benzimidazoles salts and Ag(I) complexes [27, 28, 29, 30, 31].

The antimicrobial activity of compounds 4h, 4iand 5fwas also reported in terms of the MIC values, defined as the lowest concentration of an antimicrobial that visibly inhibits the growth of the bacteria after overnight incubation.

As shown in Table 4, Silver complex 5fshowed better activity than ampicillin against L. monocytogenes, Salmonella Typhimuriumand M. luteuswith an MIC of 0.0058, 0.0034, and 0.0034 mg mL − 1, respectively. The NHC precursor 4igave a good result with an MIC of 0.041 mgmL−1 against Salmonella Typhimurium.The other compound performed poorly.

Advertisement

7. Cytotoxic activities

Salts (4a-j) and Ag(I) complexes (5a-j) were screened for their in vitro anticancer activities on human cancer cell lines MCF7 and MDA-MB-231 using the MTT test. The results are given in Table 5.

Anticancer activity
IC50/ (μg mL−1)
CompoundsMCF7MDA-MB-231
5a4.2 ± 3.54.3 ± 3.3
5b4.1 ± 3.62.6 ± 4.3
5c3.2 ± 3.12.7 ± 5.9
5d1.8 ± 3.115 ± 2.8
5e4.2 ± 1.80.0 ± 00
5f0.69 ± 3.21.94 ± 2.6
5g1.4 ± 4.13.4 ± 2.9
5h2.1 ± 3.22.7 ± 2.9
5i0.63 ± 3.11.96 ± 2.5
5j1.4 ± 4.13.5 ± 2.9
4a2.1 ± 3.22.8 ± 2.8
4bNANA
4c3.2 ± 5.96.2 ± 3.2
4dNA5.2 ± 3.1
4e0.6 ± 2.93.1 ± 5.9
4f> 100> 100
4g> 100> 100
4h> 100> 100
4i> 100> 100
4j> 100> 100
TetracyclinaNTNT

Table 5.

Anticancer activity of synthesized of benzimidazoles salts [27, 28, 29, 30, 31] 4a-4jand Ag(I) complexes 5a-5j.

The concentration was 30 μg. NA: not active; IC50: half maximal inhibitory concentration; MCF7 and MDA-MB-231: human cancer cell lines; NT: not tested. Values are mean value ± standard deviation of three different replicates.

The cytotoxicity of 5iand 5fwas higher in MCF7 with half-maximal inhibitory concentration (IC50) values of 0.63 and 0.69 μg mL−1, respectively, as compared to their activity on MDA-MB-231 cells. Complexes 5jand 4awere also determined to be toxic towards MCF7 and MDA-MB-231 with values of (IC50) 2.1 and 2.8 μg mL − 1 respectively. While, the compound 4d was inactive against MCF7.

Advertisement

8. Conclusions

In summary, a series of Ag(I) complexes were synthesized and characterized using different spectroscopic and analytical techniques. Antimicrobial properties of all Ag(I) complexes were evaluated against four Gram-negative, three Gram-positive bacterial strains and two fungal strains. New silver complexes showed high antibacterial activity compared with the precursors against gram (+)/(−) bacteria and fungi strains. Various substituents on nitrogen atoms have a different effect on antimicrobial activity. In addition, the Ag(I) complexes 5iand 5fshowed good antitumor activity against MDA-MB-231, and MCF-7 cell lines. Moreover, further studies focused on the synthesis of (benz)imidazol-2-ylidene-based silver-complexes and their medical applications as potential metallopharmaceutical agents are currently underway by our research group.

References

  1. 1. Arduengo AJ III, Harlow RL, Kline M. A stable crystalline carbene. Journal of the American Chemical Society. 1991;113(1):361-363
  2. 2. Benhamou L, Chardon E, Lavigne G, Bellemine Laponnaz S, Cesar V. Synthetic routes to N-heterocyclic carbene precursors. Chemical Reviews. 2011;111(4):2705-2733
  3. 3. Díez-Gonzalez S, Marion N, Nolan SP. N-heterocyclic carbenes in late transition metal catalysis. Chemical Reviews. 2009;109(8):3612-3676
  4. 4. Enders D, Niemeier O, Henseler A. Organocatalysis by N-heterocyclic carbenes. Chemical Reviews. 2007;107(12):5606-5655
  5. 5. Fortman GC, Nolan SP. N-Heterocyclic carbene (NHC) ligands and palladium in homogeneous cross-coupling catalysis: A perfect union. Chemical Society Reviews. 2011;40(10):5151-5169
  6. 6. Hopkinson MN, Richter C, Schedler M, Glorius F. An overview of N-heterocyclic carbenes. Nature. 2014;510:((7506)485-496
  7. 7. Peris E, Crabtree RH. Recent homogeneous catalytic applications of chelate and pincer N-heterocyclic carbenes. Coordination Chemistry Reviews. 2004;248(21-24):2239-2246
  8. 8. Małecki P, Gajda K, Ablialimov O, Malinska M, Gajda R, Wozniak K, et al. Hoveyda–Grubbs-type precatalysts with unsymmetrical N-heterocyclic carbenes as effective catalysts in olefin metathesis. Organometallics. 2017;36(11):2153-2166
  9. 9. Meng G, Szostak M. Palladium/NHC (NHC= N-heterocyclic carbene)-catalyzed B-alkyl suzuki cross-coupling of amides by selective N–C bond cleavage. Organic Letters. 2018;20(21):6789-6793
  10. 10. Tian X, Lin J, Zou S, Lv J, Huang Q, Zhu J, et al. [Pd (IPr* R)(acac) Cl]: Efficient bulky Pd-NHC catalyst for Buchwald-Hartwig CN cross-coupling reaction. Organometallic Chemistry. 2018;861:125-130
  11. 11. Karataş MO, Günal S, Mansur A, Alıcı B, Özdemir İ. Catechol-bearing imidazolium and benzimidazolium chlorides as promising antimicrobial agents. Archiv der Pharmazie. 2020;353(6):e2000013
  12. 12. Shi S, Nolan SP, Szostak M. Well-defined palladium (II)–NHC precatalysts for cross-coupling reactions of amides and esters by selective N–C/O–C cleavage. Accounts of Chemical Research. 2018;51(10):2589-2599
  13. 13. Domyati D, Latifi R, Tahsini L. Sonogashira-type cross-coupling reactions catalyzed by copper complexes of pincer N-heterocyclic carbenes. Journal of Organometallic Chemistry. 2018;860:98-105
  14. 14. Karataş MO, Giuseppe AD, Passarelli V, Alıcı B, Pérez-Torrente JJ, Oro LA, et al. Pentacoordinated rhodium (I) complexes supported by coumarin-functionalized N-heterocyclic carbene ligands. Organometallics. 2018;37(2):191-202
  15. 15. Karataş MO. Cycloheptyl substituted N-heterocyclic carbene PEPPSI-type palladium complexes with different N-coordinated ligands: involvement in Suzuki-Miyaura reaction. Journal of Organometallic Chemistry. 2019;899:120906
  16. 16. Kaloğlu M, Kaloğlu N, Günal S, Özdemir İ. Synthesis of N-heterocyclic carbene-based silver complexes and their antimicrobial properties against bacteria and fungi. Journal of Coordination Chemistry. 2021:1-17
  17. 17. Özdemir İ, Demir Düşünceli S, Kaloğlu N, Achard M, Bruneau C. Synthesis of ruthenium N-heterocyclic carbene complexes and their catalytic activity for β-alkylation of tertiary cyclic amines. Journal of Organometallic Chemistry. 2015;799:311-315
  18. 18. Şahin Z, Gürbüz N, Özdemir İ, Şahin O, Büyükgüngör O, Achard M, et al. Synthesis of ruthenium N-heterocyclic carbene complexes and their catalytic activity for β-alkylation of tertiary cyclic amines. Organometallics. 2015;34(11):2296-2304
  19. 19. Şahin N, Özdemir N, Gürbüz N, Özdemir İ. Novel N-Alkylbenzimidazole-Ruthenium (II) complexes: Synthesis and catalytic activity of N-alkylating reaction under solvent-free medium. Applied Organometallic Chemistry. 2019;33(2):e4704
  20. 20. Kaloğlu WJ, Kaloğlu M, Tahir MN, Arıcı C, Bruneau C, Doucet H, et al. Synthesis of N-heterocyclic carbene-palladium-PEPPSI complexes and their catalytic activity in the direct CH bond activation. Journal of Organometallic Chemistry. 2018;867:404-412
  21. 21. Lin JCY, Huang RTW, Lee CS, Bhattacharyya A, Hwang WS, Lin IJB. Coinage metal− N-heterocyclic carbene complexes. Chemical Reviews. 2009;109(8):3561-3598
  22. 22. Mnasri A, Mejri A, Al-Hazmy SM, Arfaoui Y, Özdemir İ, Gürbüz N, et al. Silver–N-heterocyclic carbene complexes-catalyzed multicomponent reactions: Synthesis, spectroscopic characterization, density functional theory calculations, and antibacterial study. Archiv der Pharmazie. 2021:e2100111
  23. 23. Achar G, Ramya VC, Upendranath K, Budagumpi S. Coumarin-tethered (benz) imidazolium salts and their silver (I) N-heterocyclic carbene complexes: Synthesis, characterization, crystal structure and antibacterial studies. Applied Organometallic Chemistry. 2017;31(11):e3770
  24. 24. Kızrak Ü, Çiftçi O, Özdemir İ, Gürbüz N, Düşünceli D, Kaloğlu M, et al. Amine-fnctionalized silver and gold N-heterocyclic carbene complexes: Synthesis, characterization and antitumor properties. Journal of Organometallic Chemistry. 2019;882:26-32
  25. 25. Hussaini SY, Haque RA, Razali MR. Recent progress in silver (I)-, gold (I)/(III)-and palladium (II)-N-heterocyclic carbene complexes: A review towards biological perspectives. Journal of Organometallic Chemistry. 2019;882:96-111
  26. 26. Mora M, Gimeno MC, Visbal R. Recent advances in gold–NHC complexes with biological properties. Chemical Society Reviews. 2019;48(2):447-462
  27. 27. Slimani I, Mansour L, Abutaha N, Harrath AH, Al-Tamimi J, Gürbüz N, et al. Synthesis, structural characterization of silver (I)-NHC complexes and their antimicrobial, antioxidant and antitumor activities. Journal of King Saud University. 2020;32(2):1544-1554
  28. 28. Nayak S, Gaonkar SL, Musad EA, Dawsar AMA. 1, 3, 4-Oxadiazole-containing hybrids as potential anticancer agents: Recent developments, mechanism of action and structure-activity relationships. Journal of Saudi Chemical Society. 2021;25(8):101284
  29. 29. Liang X, Luan S, Yin Z, He M, He C, Yin L, et al. Recent advances in the medical use of silver complex. European Journal of Medicinal Chemistry. 2018;157:62-80
  30. 30. Asekunowo PO, Haque RA, Razali MR, Avicor SW, Wajidi MFF. Synthesis and characterization of nitrile functionalized silver (I)-N-heterocyclic carbene complexes: DNA binding, cleavage studies, antibacterial properties and mosquitocidal activity against the dengue vector, Aedes albopictus. European Journal of Medicinal Chemistry. 2018;150:601-615
  31. 31. Habib A, Iqbal MA, Bhatti HN, Shahid M. Effect of ring substitution on synthesis of benzimidazolium salts and their silver (I) complexes: Characterization, electrochemical studies and evaluation of anticancer potential. Transition Metal Chemistry. 2019;44(5):431-443
  32. 32. Russell AD, Hugo WB. 7 antimicrobial activity and action of silver. Progress in Medicinal Chemistry. 1994;31:351-370
  33. 33. Feng QL, Wu J, Chen GQ, Cui FZ, Kim TN, Kim JO. A mechanistic study of the antibacterial effect of silver ions on Escherichia coli and Staphylococcus aureus. Journal of Biomedical Materials Research. 2000;52(4):662-668
  34. 34. Lansdown AB. Microbial multidrug resistance (mdr) and Oligodynamic silver. Journal of Wound Care. 2002;11:125-130
  35. 35. Şahin N, Semeril D, Brenner E, Matt D, Özdemir İ, Kaya C, et al. Subtle steric effects in nickel-catalysed Kumada–Tamao–Corriu cross-coupling using resorcinarenyl-imidazolium salts. European Journal of Organic Chemistry. 2013(20):4443-4449
  36. 36. Şahin N, Semeril D, Brenner E, Matt D, Özdemir İ, Kaya C, et al. Resorcinarene-functionalised imidazolium salts as ligand precursors for palladium-catalysed Suzuki–Miyaura cross-couplings. ChemCatChem. 2013;5(5):1116-1125
  37. 37. Chinnabattigalla S, Dakoju RK, Gedu SJ. Recent advances on the synthesis of flavans, isoflavans, and neoflavans. Journal of Heterocyclic Chemistry. 2020;58(2):415-441. DOI: 10.1002/jhet.4176
  38. 38. Lu Y, Yang J, Wang X, Ma Z, Li S, Liu Z, et al. Research progress in use of traditional Chinese medicine for treatment of spinal cord injury. Biomedicine & Pharmacotherapy. 2020;127:110136
  39. 39. Al-Mulla A. A review: Biological importance of heterocyclic compounds. Der Pharma Chemica. 2017;9(13):141-147
  40. 40. Jethava DJ, Borad MA, Bhoi MN, Acharya PT, Bhavsar ZA, Patel HD. New dimensions in triazolo [4, 3-a] pyrazine derivatives: The land of opportunity in organic and medicinal chemistry. Arabian Journal of Chemistry. 2020;13(12):8532-8591
  41. 41. Rabuffetti M, Bavaro T, Semproli R, Cattaneo G, Massone M, Morelli CF, et al. Synthesis of ribavirin, tecadenoson, and cladribine by enzymatic transglycosylation. Catalysts. 2019;9(4):355
  42. 42. Sun Y, Jiang H, Wu W, Zeng W, Wu X. Copper-catalyzed synthesis of substituted benzothiazoles via condensation of 2-aminobenzenethiols with nitriles. Organic Letters. 2013;15(7):1598-1601
  43. 43. Tagg JR, McGiven AR. Assay system for bacteriocins. Applied Microbiology 1971;21(5):943
  44. 44. National Committee for Clinical Laboratory Standards (NCCLS). M7-A6: Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. 6th ed. Wayne: NCCLS; 2005
  45. 45. National Committee for Clinical Laboratory Standards (NCCLS). M38-P: Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi. Wayne: NCCLS; 1998
  46. 46. Gulluce M, Sahin F, Sokmen M, Ozer H, Daferera D, Sokmen A, et al. Antimicrobial and antioxidant properties of the essential oils and methanol extract fromMentha longifoliaL. ssp.longifolia. Food Chemistry. 2007;103(4):1449-1456
  47. 47. Kirby AJ, Schmidt RJ. Antimicrobial and antioxidant properties of the essential oils and methanol extract fromMentha longifoliaL. ssp.longifolia. Journal of Ethnopharmacology 1997;56(2):103-108
  48. 48. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Journal of Immunological Methods. 1983;65(1-2):55-63
  49. 49. Miles AA, Misra SS, Irwin JO. The estimation of the bactericidal power of the blood. Epidemiology & Infection. 1938;38(6):732-749
  50. 50. Zonouzi A, Mirzazadeh R, Safavi M, Kabudanian SA, Emami S, Foroumadi A. 2-amino-4-(nitroalkyl)-4h-chromene-3-carbonitriles as new cytotoxic agents. Iranian Journal of Pharmaceutical Research. 2013;12(4):679
  51. 51. Asekunowo PO, Haque RA, Razali MR, Budagumpi S. Benzimidazole-based silver (I)–N-heterocyclic carbene complexes as anti-bacterials: Synthesis, crystal structures and nucleic acids interaction studies. Applied Organometallic Chemistry. 2015;29(3):126-137
  52. 52. De Fremont P, Scott NM, Stevens ED, Rammnial T, Lightbody OC, Macdonald CLB, et al. Synthesis of well-defined N-heterocyclic carbene silver (I) complexes. Organometallics. 2005;24(26):6301-6309
  53. 53. Chiu PL, Chen CY, Lee CC, Hsieh MH, Chuang CH, Lee HM. Structural variations in novel silver (I) complexes with bitopic pyrazole/N-heterocyclic carbene ligands. Inorganic Chemistry. 2006;45(6):2520-2530
  54. 54. Slimani I, Chakchouk-Mtibaa A, Mellouli L, Mansour L, Ozdemir I, et al. Novel N-heterocyclic carbene silver (I) complexes: Synthesis, structural characterization, antimicrobial and cytotoxicity potential studies. Journal of the Brazilian Chemical Society. 2020;31:2058-2070
  55. 55. Liu W, Gust R. Metal N-heterocyclic carbene complexes as potential antitumor metallodrugs. Chemical Society Reviews 2013;42(2):755-773.
  56. 56. Lansdown ABG. Silver I: its antibacterial properties and mechanism of action. Journal of Wound Care. 2014;11(4):125-130
  57. 57. Slimani I, Mansour L, Abutaha N, Halim Harrath A, Al-Tamimi J, Gürbüz N, et al. Synthesis, structural characterization of silver (I)-NHC complexes and their antimicrobial, antioxidant and antitumor activities. Journal of King Saud University-Science. 2020;32(2):1544-1554
  58. 58. Chen W, Liu F. Synthesis and characterization of oligomeric and polymeric silver-imidazol-2-ylidene iodide complexes. Journal of Organometallic Chemistry. 2003;673(1-2):5-12
  59. 59. Lin IJ, Vasam CS. Silver (I) N-heterocyclic carbenes. Comments on Inorganic Chemistry. 2004;25(3-4):75-129
  60. 60. Asekunowo PO, Rosenani AH, Mohd RR. Reviews in Inorganic Chemistry. 2017;37:29-50
  61. 61. Hayes JM, Viciano M, Peris E, Ujaque G, Lledós A. Mechanism of formation of silver N-heterocyclic carbenes using silver oxide: A theoretical study. Organometallics. 2007;26(25):6170-6183
  62. 62. Slawson RM, Van Dyke MI, Lee H, Trevors JT. Germanium and silver resistance, accumulation, and toxicity in microorganisms. Plasmid. 1992;27(1):72-79
  63. 63. Zhao G, Stevens SE. Multiple parameters for the comprehensive evaluation of the susceptibility ofEscherichia colito the silver ion. Biometals. 1998;11(1):27-32
  64. 64. Achar G, Agarwal P, Brinda KN, Małecki JG, Keri RS, Budagumpi S. Ether and coumarin–functionalized (benz) imidazolium salts and their silver (I)–N–heterocyclic carbene complexes: Synthesis, characterization, crystal structures and antimicrobial studies. Journal of Organometallic Chemistry. 2018;854:64-75
  65. 65. Achar G, Shahinia CR, Patil SA, Malecki JG, Pan SH, Lan A, et al. Sterically modulated silver (I) complexes of coumarin substituted benzimidazol–2–ylidenes: Synthesis, crystal structures and evaluation of their antimicrobial and antilung cancer potentials. Journal of Inorganic Biochemistry. 2018;183:43-57
  66. 66. Adhikary SD, Jhulki L, Seth S, Kundu A, Bertolasi V, Mitra P, et al. Synthetic strategy of diflurophosphate-bridgedbimetallic N- heterocycliccarbenecomplexes: Synthesis, structures and photoluminescence of picolyl-substituted alkylbenzimidazolylidene ligands. Inorganica Chimica Acta. 2012;384:239-246
  67. 67. Sánchez OS, Gonzalez S, Higuera-Padilla AR, Leon Y, Coll D, Fernandez M, et al. Remarkable in vitro anti-HIV activity of new silver(I)e and gold(I)-N- heterocyclic carbene complexes. Synthesis, DNA binding and biological evaluation. Polyhedron. 2016;110:14-23
  68. 68. Arduengo AJ III, Dias HVR, Calabrese JC, Davidson F. Homoleptic carbine silver(I) and carbine-copper(I) complexes. Organometallics. 1993;12(9):3405-3409
  69. 69. Arduengo AJ III, Harlow RL. Stable crystalline carbine. Journal of the American Chemical Society. 1991;113(1):361-363
  70. 70. Balcan S, Balcan M, Cetinkaya B. Poly(l-lactide) initiated by silver N- heterocyclic carbene complexes: Synthesis, characterization and properties. Polymer Bulletin. 2013;70(12):3475-3485
  71. 71. Baquero EA, Silbestri GF, Gomez-sal P, Flores JC, Jesús E. Sulfonatedwater-soluble N-heterocyclic carbine silver(I) complexes: Behavior in aqueousmedium and as NHC-transfer agent to platinum(II). Organometallics. 2013;32(9):2814-2826
  72. 72. Boubakri L, Mansour L, Harrath AH, Özdemir I, Yasar S, Hamdi N.N-heterocyclic carbene-Pd (II)-PPh3 complexes a new highly efficient catalyst system for the Sonogashira cross-coupling reaction: Synthesis, characterization and biological activities. Journal of Coordination Chemistry. 2018;71(2):183-199
  73. 73. Cavallo L, Correa A, Costabile C, Jacobsen H. Steric and electronic effects in the bonding of N-heterocyclic ligands to transition metals. Journal of Organometallic Chemistry. 2005;690(24-25):5407-5413

Written By

Ichraf Slimani, Khaireddine Dridi, Ismail Özdemir, Nevin Gürbüz and Naceur Hamdi

Submitted: October 14th, 2021 Reviewed: December 9th, 2021 Published: February 16th, 2022